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Cancer Cell. 2017 Feb 13;31(2):286-299. doi: 10.1016/j.ccell.2017.01.006.

Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis.

Author information

1
Pharmacology Graduate Training Program, Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Louis V. Gerstner, Jr., Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7
Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Anti-Tumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9
Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA.
10
Epizyme, Inc., 400 Technology Square, Cambridge, MA, USA.
11
Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, OH, USA.
12
Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
13
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rudinc@mskcc.org.
14
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: poirierj@mskcc.org.

Abstract

Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.

KEYWORDS:

EPZ011989; EZH2; SLFN11; TWIST1; acquired resistance; cisplatin; etoposide; patient-derived xenograft; small cell lung cancer

PMID:
28196596
PMCID:
PMC5313262
DOI:
10.1016/j.ccell.2017.01.006
[Indexed for MEDLINE]
Free PMC Article

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